Born in The Bronx, New York, Buono was raised in a blue-collar family and decided at an early age to make acting her life's ambition. At 11, she showed her connection to her family's work ethic by answering a casting call ad for Harvey Fierstein's "Spookhouse" and landing the role, without any assistance from her family or other adults. Buono began landing roles on television and the New York stage while in her teens and early twenties, and earned a Daytime Emmy nomination as a young victim of sexual abuse in Abby, My Love (1991) (CBS, 1991), which aired as part of the CBS Schoolbreak Special (1984). She soon graduated to minor roles in Stephen Gyllenhaal's Waterland (1992), with Jeremy Irons and Ethan Hawke; as an illegal immigrant in The Cowboy Way (1994), with Woody Harrelson and Kiefer Sutherland; and in Noah Baumbach's much-loved indie comedy, Kicking and Screaming (1995), which reunited her with her "Abby, My Love" co-star, Josh Hamilton. While cultivating her acting career, Buono also graduated from Columbia University with a double major in English and political science in 1995, which she earned in just three years.

After graduation, Buono concentrated largely on character roles in independent films and on television. She was the wife and confidante of prison guard Robert Sean Leonard, who served as an earpiece for monstrous 1930s criminal Carl Panzram (James Woods) in Killer: A Journal of Murder (1995), before playing an accident-prone opera singer in love with a young man (Gibson Frazier) with Jazz-Era affectations in the offbeat Man of the Century (1999). She soon added behind-the-camera credits to her expanding resume, including writer/director on the short, Baggage (1997), with Liev Schreiber and Minnie Driver, and served as co-producer and star of the comedy, Two Ninas (1999), about a pair of similarly monikered women (Buono and Amanda Peet) who fell for a very unlucky man. She continues to write and co-wrote "When the Cat's Away" (1999), with Brad Anderson, and wrote an adaptation of F. Scott Fitzgerald's first novel, "This Side of Paradise".

Buono's screen credits grew more obscure at the launch of the new millennium - art house and film festival circles saw the lesbian drama, Chutney Popcorn (1999), Attention Shoppers (2000), Happy Accidents (2000) with Marisa Tomei and Vincent D'Onofrio. She soon turned to television for wider exposure, and earned it through supporting roles on high profile series like Third Watch (1999) and The Sopranos (1999). In 2007, she joined the cast of the cult favorite, The Dead Zone (2002) (USA, 2002-2007) as Sheriff Anna Turner, who investigated the death of her predecessor (Chris Bruno).

During this period, Buono maintained her screen career in features as varied as Ang Lee's Hulk (2003), playing David Banner's mother, who was killed by his genetically-induced rage, and Beer League (2006), and Artie Lange's hapless lay-about love interest. In 2010, she appeared as the divorced mother of Kodi Smit-McPhee in Let Me In (2010), the critically-praised American remake of the Swedish vampire movie, Let the Right One In (2008). That same year, she landed her most widely seen role-to-date on Mad Men (2007), playing Dr. Faye Miller. For her efforts, Buono received an Emmy Award nomination for Outstanding Guest Actress in a Drama Series in 2011.